Off-label prescribing of hormones in gender dysphoria should be investigated

Det här är en översättning av Karin Svens och Sven Románs debattartikel ”Off label-förskrivning av hormoner vid könsdysfori bör utredas” publicerad i Läkartidningen. This is a translation of an article by Karin Svens och Sven Román published in Läkartidningen.

Karin Svens, PhD, ERT (European registered toxicologist); consultant, chemical risk assessment and drug development

Sven Román, child and adolescent psychiatrist; psychiatrist consultant, own company, Stockholm

Recently, the Anova Clinic in Stockholm held its regular information day on gender dysphoria. One clear message from this meeting was that it is essentially risk-free for girls to take testosterone (and for estrogen boys) from their teens and throughout adult life. If the clinic provides the same information to patients, they are communicating serious and potentially damaging misinformation.

The extensive off-label prescription of sex-controlled hormones (estrogen for boys and testosterone for girls) involves both known and unknown health risks. In 2018, 724 people under 25 were treated with sex-controlled hormones [1]. There are most likely many more, as legal gender change darkens the statistics.

In recent years, more girls (15-19 years) than boys have been treated with testosterone in Stockholm, Sweden. In addition, a significant increase in patients at gender dysphoria has been reported [2, 3]. Last year (2018), 71 girls were treated with testosterone – an 18-fold increase over the years 2008–2011 (an average of four girls / year).

To safeguard young people’s future health, a risk assessment of sex-controlled hormones is both important and urgent. The Swedish Drug Agency considers that extensive off-label use should be included in clinical studies to build up knowledge [4]. We certainly do not have a full risk assessment and no clinical trial initiated.

Long-term use of the relatively high doses of testosterone used in gender correction is poorly researched. Both preclinical and clinical safety studies are lacking in women. Thus, regulatory approval is lacking.

Systematic follow-ups of side effects is also another area that is lacking, since the drug companies’ reports only cover approved indications. Adverse drug reporting by healthcare professionals is sporadic at best [5, 6]. There is no report on off-label use of hormones in the Swedish Drug Agency’s adverse reaction database.

Already in 1987, the International Agency for Research on Cancer (IARC) classified anabolic steroids, including testosterone, as likely to be human carcinogens (group 2A; the second highest rating), which means that testosterone is proven to be carcinogenic in animals and probably also in humans [7]. Testosterone is classified as reproductively harmful by the US Medicines Agency (FDA) due to its fetal damaging effects, and since 2016 also as addictive [8].

Data from sportswomen from Easter Europe who were exposed to various anabolic steroids (including testosterone) for a time in adolescence show a range of side effects in addition to masculinizing effects: including polycystic ovarian syndrome, severe liver injury, and delayed growth (in teens) [9].

An increased incidence of myocardial infarction and possibly stroke was seen in transmitters treated with testosterone after a follow-up period of just over four years [10]. After 12 weeks of use, testosterone induces mitochondrial dysfunction in transmitters [11].

Drug-induced mitochondrial dysfunction can be linked to many different disease states [12, 13]. The intended life-long hormone exposure in sex dysphoria patients and that the treatment starts at a young age are inherently possible risk factors. The side effects seen with short use and higher doses then risk coming at significantly lower doses.

In April 2019, the Swedish Medical and Ethical Council (Smer) proposed that the Ministry of Social Affairs should commission three authorities to review gender dysphoria and the treatment of children and young people. The Agency’s task – to examine off-label prescribing of sex-controlled hormones – has not been initiated [14]. Given the obvious risks, one might wonder why?

Treatment with sex-controlled hormones in young patients (under 25 years) should be discontinued and the risks investigated. Only if and when the benefit is deemed to exceed the risks should it be resumed.

Potential bonds or conflicts: Karin Svens is the parent of an adult transsexual who is satisfied with her transition.